DESCRIPTION (Adapted from the applicant's abstract and specific aims): Neutrophil elastase is a potent proteolytic enzyme believed to be important in the host defense and inflammatory functions of the polymorphonuclear leukocyte (PMN). Abnormal expression of this proteinase may lead to a variety of destructive diseases including pulmonary emphysema. The role of human neutrophil elastase (HNE) in the pathogenesis of the usual form of emphysema associated with cigarette smoking is unclear. In fact, the predominant inflammatory cell in the lower airways of smokers is the alveolar macrophage rather than the neutrophil. In addition to HNE, other neutrophil proteinases with elastolytic activity and several macrophage elastases have been identified that may contribute to the lung destruction associated with emphysema. The long term goal of this project is to directly determine the role of neutrophil elastase in the pathogenesis of pulmonary emphysema related to cigarette smoking. The specific aims are to: 1) determine the organization of the mouse neutrophil elastase genomic locus and generate cDNA probes and antibodies to mouse neutrophil elastase; 2) generate lines of mNE-deficient (mNE-/-) mice; 3) use mNE-/- mice to determine the contribution of neutrophil elastase to normal neutrophil functions; and 4) define the capacity of mNE-/- mice vs. normal littermates (mNE+/+) to develop pulmonary emphysema related to cigarette smoking.